Homogeneous ophthalmic composition

ABSTRACT

This application is directed to a homogeneous solution of an aqueous, topical composition useful for the treatment of infection and/or for the treatment of inflammation due to trauma to tissue. Specifically, this application relates to a homogeneous, aqueous composition of a quinolone antibiotic and an anti-inflammatory agent.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Continuation of U.S. Non-Provisional patentapplication Ser. No. 17/018,040, filed Sep. 11, 2020 and titled“Homogeneous Ophthalmic Composition,” which is a Continuation-in-Part ofU.S. Non-Provisional patent application Ser. No. 16/158,904, filed Oct.12, 2018 and titled “Homogeneous Ophthalmic Composition,” which issuedas U.S. Pat. No. 10,780,100 on Sep. 22, 2020 and is a Continuation ofU.S. Non-Provisional patent application Ser. No. 14/846,752, filed Sep.5, 2015 and titled “Homogeneous Ophthalmic Composition,” which issued asU.S. Pat. No. 10,130,639 on Nov. 20, 2018, the entire disclosure of eachof which is hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

REFERENCE TO SEQUENCE LISTING OR COMPUTER PROGRAM LISTING APPENDIX

Not Applicable.

BACKGROUND OF THE INVENTION

A cataract is an opaque portion of the lens of the eye. A cataract canbe localized to a small region of the lens or it can be diffuse whereinthe entire lens appears cloudy. It is the primary cause of visualimpairment worldwide, and also the leading cause of vision loss in theUnited States. An estimated 20.5 million Americans aged 40 years andolder have a cataract in one or both eyes. This number is expected toincrease to 30.1 million by 2020.

Cataracts can occur at any age and can be present at birth. Causes ofcataracts include age, heredity, trauma, inflammation, metabolicdisorders, smoking, alcohol consumption, nutritional deficiencies,certain medications, and ultra-violet radiation. Fortunately, cataractsurgery is available to reduce this visual impairment.

Cataract surgery involves removal of the entire eye lens withconcomitant replacement of the lens with an artificial lens. Accordingto the WHO, the number of cataract surgeries performed in 2010 wasestimated to be around 20 million and this number is expected to reach32 million by 2020. About 3 million cataract surgeries are performedeach year in the U.S. alone, making it the most common surgery forAmericans over age 65. The amount spent on cataract surgeries in theU.S. is several billion dollars per year.

Proper post-operative care is critical to ensure an optimal visualoutcome after cataract surgery. It is during the period ofpost-operative care that most complications occur, such as bacterialinfection, uncontrolled elevated intraocular pressure (IOP), ocularhypertension, malignant glaucoma, wound leakage, cystoid macular edema(GEM), endophthalmitis, iris prolapse, intraocular lens dislocation,hemorrhage, and severe inflammation. The post-operative regimen normallyincludes restricted activity and the application of a multitude oftopical medications to the eye at numerous times per day for 1-8 weeksdepending on the patient's situation and the nature of the surgery.These topical medications generally include an antibiotic to be applied1-4×per day; a steroidal agent to be applied 1-4×per day, and/or anon-steroidal agent to be applied 1-4×per day, with a 5 minute gapbetween the application of the each medication to the eye. The time gapbetween doses helps to diminish the likelihood that the first dose willbe washed out by the second dose because of insufficient time forabsorption of the first dose.

Most people, especially the elderly who undergo the majority of cataractsurgeries, experience difficulty in complying with such a complicatedmedication regimen. For example, it is difficult for some people to putdrops in their eyes, which is amplified by the need to do so four timesa day with three separate solutions for a total of 1-8 weeks. Asmentioned above, there is a problem wash out of the first medicine byapplication of the second medicine if the required wait time is notadhered to. Another problem is that one or more of the three bottles maybe misplaced, contaminated, or damaged. Yet another problem is thedifficulty in keeping track of which medicine was already instilled inthe eye when there are three bottles of medicine to be used in onesitting. Still another problem is that the length of time the medicatingprocess takes is long because there is a wait time of 5 minutes aftereach drop is instilled, which process totals about an hour a day devotedto instilling drops to the eye. Also, another problem is that attemptsat combining a quinoline antibiotic with an anti-inflammatory agentresults in formulations containing a precipitate and/or particulatematter as in a suspension so that there are none commercially availableas an aqueous solution.

Thus, there is an urgent need for an easier-to-follow medication regimenin order to increase patient compliance and to ensure better visualoutcomes. The composition described in this application solves thisproblem by combining all three previously separate medications into asingle, homogeneous solution, which will be significantly lesscomplicated for the patient to use and will result in better complianceand visual outcomes.

Unexpectedly, preliminary results indicate that use of the compositiondescribed herein, which contains all of the active ingredients withinone solution, seems to reduce the incidence of cystoid macular edema(CME) more effectively than the use of separate solutions of each of theactive ingredients. CME is the most prevalent cause of vision loss aftercataract surgery, with up to 58% of patients having some angiographicevidence of CME and there is no reliable treatment for the prevention ortreatment of CME following cataract surgery.

BRIEF SUMMARY

This Brief Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used as an aid in determining the scope of the claimed subjectmatter.

Compositions including an aqueous, homogeneous solution of an antibioticor mixtures thereof and an anti-inflammatory agent or mixtures thereofare disclosed herein. The pH of the compositions disclosed herein canrange from about 4.5 to about 8.5.

In one embodiment, a composition can contain 0.5% by weight moxifloxacinhydrochloride, 0.07% bromfenac sodium sesquihydrate, 0.1% by weightdexamethasone sodium phosphate, 0.01% by weight edetate disodiumdihydrate, 0.1% by weight hydroxyethyl cellulose, 0.5% by weightbenzalkonium chloride, hydrochloric acid to adjust pH, sodium hydroxideto adjust pH, and 1.8% glycerin.

In another embodiment, a composition can contain 0.5% by weightmoxifloxacin, 0.035% bromfenac, 0.1% by weight dexamethasone phosphate,0.01% by weight edetate disodium dihydrate, hydroxyethyl cellulose toadjust viscosity (e.g., to about 4800 cps), 0.005% by weight/volume(“w/v”) benzalkonium chloride (e.g., 50 ml of 1% by weight benzalkoniumchloride solution in a 10,000 ml batch), hydrochloric acid to adjust pH,sodium hydroxide to adjust pH, and 1.8% glycerin.

DETAILED DESCRIPTION

The details of one or more embodiments of the presently disclosedsubject matter are set forth in this document. Modifications toembodiments described in this document, and other embodiments, will beevident to those of ordinary skill in the art after a study of theinformation provided herein. The information provided in this document,and particularly the specific details of the described exemplaryembodiments, is provided primarily for clearness of understanding and nounnecessary limitations are to be understood therefrom. In case ofconflict, the specification of this document, including definitions,will control.

While the terms used herein are believed to be well understood by one ofordinary skill in the art, definitions are set forth herein tofacilitate explanation of the subject matter disclosed herein.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the subject matter disclosed herein belongs. Althoughany methods, devices, and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentlydisclosed subject matter, representative methods, devices and materialsare now described.

The terms “a”, “an”, and “the” refer to “one or more” when used in thisapplication, including the claims Thus, for example, reference to “asteroid” includes a plurality of particles of the steroid, and so forth.The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

All references to singular characteristics or limitations of the presentdisclosure shall include the corresponding plural characteristic(s) orlimitation(s) and vice versa, unless otherwise specified or clearlyimplied to the contrary by the context in which the reference is made.

All combinations of method or process steps as used herein can beperformed in any order, unless otherwise specified or clearly implied tothe contrary by the context in which the referenced combination is made.

The compositions and methods of the present disclosure, includingcomponents thereof, can comprise, consist of, or consist essentially ofthe essential elements and limitations of the embodiments describedherein, as well as any additional or optional components or limitationsdescribed herein or otherwise useful.

The phrase “in one embodiment,” as used herein does not necessarilyrefer to the same embodiment, although it may. Conditional language usedherein, such as, among others, “can”, “might”, “may”, “e.g.,” and thelike, unless specifically stated otherwise, or otherwise understoodwithin the context as used, is generally intended to convey that certainembodiments include, while other embodiments do not include, certainfeatures, elements and/or states.

Unless otherwise indicated, all numbers expressing physical dimensions,quantities of ingredients, properties such as reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about”. Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thisspecification and claims are approximations that can vary depending uponthe desired properties sought to be obtained by the presently disclosedsubject matter.

As used herein, the term “about,” when referring to a value or to anamount of mass, weight, time, volume, concentration, percentage or aphysical dimension such as length, width, or diameter, is meant toencompass variations of in some embodiments +−40% or more, in someembodiments +−20%, in some embodiments +−10%, in some embodiments +−5%,in some embodiments +−1%, in some embodiments +−0.5%, and in someembodiments +−0.1% from the specified value or amount, as suchvariations are appropriate to perform the disclosed methods.

As used herein, ranges can be expressed as from “about” one particularvalue, and/or to “about” another particular value. It is also understoodthat there are a number of values disclosed herein, and that each valueis also herein disclosed as “about” that particular value in addition tothe value itself. For example, if the value “10” is disclosed, then“about 10” is also disclosed. It is also understood that each unitbetween two particular units are also disclosed. For example, if 10 and15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

The present invention contemplates an aqueous, homogeneous solution ofan antibiotic or mixtures thereof and an anti-inflammatory agent ormixtures thereof. Also contemplated is a method of treatment of anophthalmic, an otic, or a nasal condition by the topical application ofthe contemplated solution to the affected tissue. The indicatedcondition may be an infection or an inflammation of tissue or may be forthe prevention of post-surgical trauma or infection, i.e., aprophylactic measure. Another contemplated embodiment is a method ofmaking the contemplated solution.

In one embodiment, the solution contains one antibiotic and oneanti-inflammatory agent. In another embodiment, the solution contains amixture of antibiotics and one anti-inflammatory agent. In yet anotherembodiment, the solution contains one antibiotic and a mixture ofanti-inflammatory agents. In still yet another embodiment, the solutioncontains a mixture of antibiotics and a mixture of anti-inflammatoryagents.

The contemplated solution is an aqueous, homogeneous solution and not asuspension. As is generally understood, a solution denotes ahomogeneous, transparent liquid that is free of particulate matter, anda suspension denotes an aqueous formulation that contains solidparticles and is not homogeneous.

Quite often, the combination of an antibiotic and an anti-inflammatoryagent results in precipitate formation so that antibiotic-steroidcombinations currently available are in the form of ointments andsuspensions. However, both of these forms of medication are problematicfor treatment of the eyes in particular. Ophthalmic ointments arecumbersome to use, do not deliver consistent levels of medication, andcan impede delivery of other ophthalmic drugs by serving as a physicaland chemical barrier due to the presence of the viscous gel vehicle.Ophthalmic suspensions require adequate agitation before each use, donot deliver consistent levels of medication, mix with tears lessrapidly, and can cause irritation due to the presence of particulates.Also, absorption of both of these forms of medication is minimal.

The concentrations of the antibiotic and the anti-inflammatory agent inthe solution will vary depending upon the activity of the particularantibiotic and the nature of the treatment, i.e., infection orprophylactic. In one embodiment, the composition contains about 0.1 toabout 1% by weight of the antibiotic or mixtures thereof and about 0.01to about 1% by weight of the anti-inflammatory agent or mixturesthereof. In another embodiment, the composition contains about 0.5 toabout 1% by weight of the antibiotic or mixtures thereof and about 0.1to about 1% by weight of the anti-inflammatory agent or mixturesthereof. In still another embodiment, the composition contains about0.5% by weight of the antibiotic or mixtures thereof and about 0.1% byweight of the anti-inflammatory agent or mixtures thereof. When thereare mixtures of anti-inflammatory agents in the composition, each ofthem is present in the range of about 0.07 to about 1% by weight. The pHof the composition ranges from about 4.5 to about 8.5. The pH of thecomposition can also be from 7.5-8.5. In some embodiments, the pH of thefinal composition can be from about 8.20 to about 8.25.

The present composition contains a quinolone antibiotic, derivativesthereof, salts thereof, or mixtures thereof. Quinolone antibioticsinclude moxifloxacin, ciprofloxacin, oflaxacin, norfloxacin,lomefloxecin, derivatives thereof, salts thereof, and mixtures thereof.In another embodiment, the antibiotic is moxifloxacin hydrochloride.

The composition also contains an anti-inflammatory agent.Anti-inflammatory agents include a non-steroidal agent, a steroidalagent, or a mixture of a non-steroidal agent and a steroidal agent. Inone embodiment, the anti-inflammatory agent comprises a steroidal agent.Common steroidal agents include dexamethasone sodium phosphate,budensonide, triamcinolone, hydrocortisone, loteprednol, prednisolone,mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone,flunisolide, derivatives thereof, and mixtures thereof. In yet anotherembodiment, the anti-inflammatory agent is dexamethasone sodiumphosphate.

In an alternative embodiment, the anti-inflammatory agent comprises anon-steroidal agent. Well-known non-steroidal agents include bromfenac,bromfenac sodium, bromfenac sodium sesquihydrate, aspirin, nabumetome,etodolac, meclofenamate, ibuprofen, flurbiprofen, diffusional,piroxicam, suproprofen, diclofenac, sulindac, oxyphenbutazone,oxaproazin, ketorolac, naproxen, nepafenac, bromfenac, mefamic acid,ketoprofen, amfenac, fenoprofen, phenylbutazone, indomethacin,cececoxib, nupafant, filaminast, salts thereof, hydrates thereof, andderivatives thereof. In one embodiment, the anti-inflammatory agent isbromfenac or a pharmaceutically acceptable salt thereof or a hydratethereof or mixtures thereof. In another embodiment, theanti-inflammatory agent is bromfenac sodium sesquihydrate. In yetanother embodiment, the anti-inflammatory agent is bromfenac sodium.

In a different embodiment, the anti-inflammatory agent is a mixture of anon-steroidal agent and a steroidal agent. For example, theanti-inflammatory agent can be a mixture of bromfenac sodium anddexamethasone sodium phosphate. As another example, theanti-inflammatory agent is a mixture of bromfenac sodium sesquihydrateand dexamethasone sodium phosphate.

Thus, one embodiment of the composition can be moxifloxacinhydrochloride and dexamethasone sodium phosphate. Another embodiment ofthe composition can be moxifloxacin hydrochloride and bromfenac sodium.Yet another embodiment can be moxifloxacin hydrochloride, bromfenacsodium sesquihydrate, and dexamethasone sodium phosphate.

The composition further can contain a pharmaceutically acceptableadditive. This additive can be a preservative, a solubility enhancer, athickener, a pH moderating agent, a buffer, a humectant, or mixturesthereof. Commonly known preservatives are contemplated herein, includinga detergent preservative, an oxidizing preservative, and anionic-buffered preservative. Examples of preservatives are edetatesodium; benzalkonium chloride; centrimonium chloride; sodium perborate;stabilized oxychlorocomplex; sorbic acid; thimersol; polyquarternium-1;polyhexamethylene biguanide; chlorobutanol; phenylethyl alcohol; methylparaben; propyl paraben; a combination of boric acid, zinc, sorbital,and propylene glycol; and mixtures thereof.

The composition can also contain a solubility enhancer. Commonsolubility enhancers include cyclodextrin, polysorbate 20, polysorbate60, polysorbate 80, Pluronic®, and mixtures thereof.

The present composition can also include a thickener. Examples ofthickeners include hydroxyethyl cellulose, methyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and mixturesthereof.

The composition can contain a pH moderating agent. Suitable pHmoderating agents are acids and bases such as sodium hydroxide,hydrochloric acid, phosphoric acid, acetic acid, and mixtures thereof.

Buffers can also be included in the composition. Appropriate buffersinclude boric acid, sodium borate, and mixtures thereof.

Furthermore, the composition can contain a humectant. The humectant canbe glycerin, sorbitol, gelatin, mannitol, dextrose, sucrose, urea, andmixtures thereof.

Also contemplated herein is a composition comprising moxifloxacinhydrochloride, dexamethasone sodium phosphate, edetate disodiumdihydrate, hydroxyethyl cellulose, benzalkonium chloride, hydrochloricacid to adjust pH, sodium hydroxide to adjust pH, and glycerin.

A composition including 0.5% by weight moxifloxacin hydrochloride, 0.08%by weight bromfenac sodium, 0.1% by weight dexamethasone sodiumphosphate, 0.01% by weight edetate disodium dihydrate, 0.1% by weighthydroxyethyl cellulose, 0.5% by weight benzalkonium chloride,hydrochloric acid to adjust pH, sodium hydroxide to adjust pH, and 1.8%by weight glycerin is contemplated herein.

Also, a composition containing 0.5% by weight moxifloxacinhydrochloride, 0.07% bromfenac sodium sesquihydrate, 0.1% by weightdexamethasone sodium phosphate, 0.01% by weight edetate disodiumdihydrate, 0.1% by weight hydroxyethyl cellulose, 0.5% by weightbenzalkonium chloride, hydrochloric acid to adjust pH, sodium hydroxideto adjust pH, and 1.8% glycerin is contemplated herein.

In addition, a composition containing 0.5% by weight moxifloxacinhydrochloride, 0.1% by weight dexamethasone sodium phosphate, 0.01%edetate disodium dihydrate, 0.1% by weight hydroxyethyl cellulose, 0.5%by weight benzalkonium chloride, hydrochloric acid to adjust pH, sodiumhydroxide to adjust pH, and 1.8% by weight glycerin is considered here.

Another composition including 0.035% by weight bromfenac sodium, 0.1% byweight dexamethasone sodium phosphate, 0.01% by weight edetate disodiumdihydrate, hydroxyethyl cellulose (4,800 cps) to adjust viscosity,0.005% w/v benzalkonium chloride, hydrochloric acid to adjust pH, sodiumhydroxide to adjust pH, 1.8% by weight glycerin, and 0.05% by weightpolysorbate 80 is contemplated herein.

Yet another composition containing 0.5% by weight moxifloxacinhydrochloride, 0.035% bromfenac sodium sesquihydrate, 0.1% by weightdexamethasone sodium phosphate, 0.01% by weight edetate disodiumdihydrate, hydroxyethyl cellulose (4,800 cps) to adjust viscosity,0.005% w/v benzalkonium chloride, hydrochloric acid to adjust pH, sodiumhydroxide to adjust pH, 1.8% glycerin, and 0.05% by weight polysorbate80 is contemplated herein.

Still yet another composition containing 0.5% by weight moxifloxacinhydrochloride, 0.1% by weight dexamethasone sodium phosphate, 0.01%edetate disodium dihydrate, hydroxyethyl cellulose (4,800 cps) to adjustviscosity, 0.005% by weight benzalkonium chloride, hydrochloric acid toadjust pH, sodium hydroxide to adjust pH, and 1.8% by weight glycerin iscontemplated here.

The composition can be designed for a range of osmolalities thoughiso-osmolal is the norm. Osmolalities range from about 175 to about 330mOsm/kg. In one embodiment, the osmolality ranges from 280 to 325mOsm/kg. The osmolality can be adjusted by the addition of salt such assodium chloride or potassium chloride or by the use of monosaccharides.

Furthermore, a method of treating an ophthalmic infection orinflammation is contemplated herein. One embodiment of the methodentails topically applying an aqueous, homogeneous solution made of anantibiotic or mixtures thereof and an anti-inflammatory agent ormixtures thereof to the eye. In one embodiment, the antibiotic ismoxifloxacin hydrochloride and the anti-inflammatory agent isdexamethasone sodium phosphate. In another embodiment, the antibiotic ismoxifloxacin hydrochloride and the anti-inflammatory agent is bromfenacsodium. In yet another embodiment, the antibiotic is moxifloxacinhydrochloride and the anti-inflammatory agent is a mixture of bromfenacsodium and dexamethasone sodium phosphate. The aqueous, homogeneoussolution of an antibiotic or mixtures thereof and an anti-inflammatoryagent or mixtures thereof can be applied topically to the eye once aday, twice a day, three times a day, or four times a day as needed withvariable durations of therapy ranging from 1-8 weeks or longer.

Moreover, a method of making an ophthalmic solution is contemplatedherein. One embodiment of the method entails dissolving moxifloxacin,dexamethasone, and sodium bromfenac each in separate receptacles ofwater with stirring to form three aqueous compositions; the pH of eachof the compositions is adjusted to pH 7.5-8.5; then hydroxyethylcellulose is added to the dexamethasone composition with stirring,followed by the addition of glycerin to the dexamethasone compositionwith stirring; followed by the addition of benzalkonium chloride to thedexamethasone composition with stirring; followed by the addition ofedetate disodium to the dexamethasone composition with stirring. The pHis adjusted to pH 7.5-8.5. Next, the dexamethasone composition is addedto the moxifloxacin composition to form a dexamethasone and moxifloxacincomposition; then, the sodium bromfenac composition is added to thedexamethasone and moxifloxacin composition with stirring. In analternative embodiment, sodium bromfenac sesquihydrate can besubstituted for sodium bromfenac.

Another embodiment of the method entails dissolving moxifloxacin,dexamethasone, and sodium bromfenac each in separate receptacles ofwater with stirring to form three aqueous compositions; the pH of eachof the compositions is adjusted to pH 8.20-8.25; then edetate disodiumis added to the dexamethasone composition with stirring, followed by theaddition of glycerin to the dexamethasone composition with stirring;followed by the addition of hydroxyethyl cellulose (4,800 cps) to thedexamethasone composition with stirring. The pH is adjusted to pH8.20-8.25. Next, polysorbate 80 is added to the bromfenac compositionwith stirring and then adjust the pH to 8.20-8.25, then the bromfenaccomposition is added to the moxifloxacin composition to form a bromfenacand moxifloxacin composition; then, the dexamethasone composition isadded to the bromfenac and moxifloxacin composition with stirring toform a dexamethasone and bromfenac and moxifloxacin composition. In analternative embodiment, sodium bromfenac sesquihydrate can besubstituted for sodium bromfenac. Finally, benzalkonium chloride isadded to the solution of dexamethasone and bromfenac and moxifloxacinwith stirring.

In another method, moxifloxacin and dexamethasone are dissolved inseparate receptacles of water with stirring to form two aqueouscompositions; the pH of each of the compositions is adjusted to pH7.5-8; then hydroxyethyl cellulose is added to the dexamethasonecomposition with stirring, followed by the addition of glycerin to thedexamethasone composition with stirring; followed by the addition ofbenzalkonium chloride to the dexamethasone composition with stirring;followed by the addition of edetate disodium to the dexamethasonecomposition with stirring. Next, the dexamethasone composition is addedto the moxifloxacin composition to form a dexamethasone-moxifloxacincomposition.

In yet another method, moxifloxacin and dexamethasone are dissolved inseparate receptacles of water with stirring to form two aqueouscompositions; the pH of each of the compositions is adjusted to pH8.20-8.25; then edetate disodium is added to the dexamethasonecomposition with stirring, followed by the addition of glycerin to thedexamethasone composition with stirring, and then hydroxyethyl cellulose(4,800 cps) is added to the dexamethasone composition with stirring.Next, the dexamethasone composition is added to the moxifloxacincomposition to form a dexamethasone-moxifloxacin composition. Finally,benzalkonium chloride is added to the solution ofdexamethasone-moxifloxacin composition with stirring. The final pH isadjusted as needed to 8.20-8.25.

The order of addition of the additives can be varied and what solutionthey are added to can be varied also as long as the pH of the solutioncontaining the active ingredients is from 7.5 to 8.5 and the pH of thefinal solution is from 7.5 to 8.5.

EXAMPLES Example 1

The following procedure was followed to make a homogeneous, aqueoussolution of moxifloxacin, sodium bromfenac sesquihydrate, anddexamethasone sodium phosphate.

Ingredients Amount Moxifloxacin hydrochloride powder 5.454 g Bromfenacsodium sesquihydrate powder 0.4025 g Dexamethasone sodium phosphatepowder 1.1 g Edetate disodium dihydrate powder 0.1 g Hydroxyethylcellulose powder (4,800 cps) 1 g Benzalkonium chloride solution(0.5%/ml) 5 ml Polysorbate 80 0.5 ml Glycerin 18.2 ml Hydrochloric acid(10% solution) for pH varies adjustment Sodium hydroxide (1% solution)for pH varies adjustment Sterile water up to 1000 ml

Preliminary attempts to combine the dry active ingredients moxifloxacinand sodium bromfenac and dexamethasone into one aqueous solution bydissolving in water resulted in solubility problems. The resultingmixture appeared hazy with particles visible to the naked eye, where theparticles settled on the bottom of the receptacle.

Therefore, the active ingredients moxifloxacin hydrochloride, sodiumbromfenac, and dexamethasone sodium phosphate, were weighed outseparately and placed into individual clear receptacles. About 300 mlsterile water was added to each receptacle with stirring. All threeactive ingredients dissolved well to form three transparent solutions.The pH of each of the solutions was then adjusted to pH 7.7-8.5 withhydrochloric acid or sodium hydroxide dropwise. Next, edetate disodiumwas added to the dexamethasone composition with stirring; followed bythe addition of glycerin to the dexamethasone composition with stirring;followed by the addition of hydroxyethyl cellulose (4,800 cps) to thedexamethasone composition with stirring. The pH of the dexamethasonecomposition was adjusted to pH 8.2. Polysorbate 80 was then added to thebromfenac composition with stirring and the pH of the bromfenaccomposition was adjusted as needed to pH 8.2. The bromfenac compositioncontaining polysorbate 80 was then added to the moxifloxacin compositionto form a bromfenac and moxifloxacin composition. The pH of thebromfenac and moxifloxacin composition was adjusted as needed to pH 8.2.The dexamethasone composition was then added to the bromfenac andmoxifloxacin composition with stirring to form a dexamethasone andbromfenac and moxifloxacin composition. The pH of the dexamethasone andbromfenac and moxifloxacin composition was adjusted as needed to pH 8.2.Last, the benzalkonium chloride was added to the solution ofdexamethasone and bromfenac and moxifloxacin with stirring, and the pHagain adjusted as needed to pH 8.2. The volume was brought up to 1000 mlwith sterile water. The solution was clear and transparent. The solutionwas aseptically filtered and placed into 5 ml sterile droptainers.Testing such as rapid scan for sterility, pyrogenicity, and potency werecarried out.

Example 2

The following procedure was followed to make a homogeneous, aqueoussolution of moxifloxacin and dexamethasone.

Ingredients Amount Moxifloxacin hydrochloride powder 5.454 gDexamethasone sodium phosphate powder 1.1 g Edetate disodium dihydratepowder 0.1 g Hydroxyethyl cellulose powder (4,800 cps) 1 g Benzalkoniumchloride solution (0.5%/ml) 5 ml Glycerin 18.2 ml Hydrochloric acid (10%solution) for pH varies adjustment Sodium hydroxide (1% solution) for pHvaries adjustment Sterile water up to 1000 ml

The active ingredients moxifloxacin hydrochloride and dexamethasonesodium phosphate were weighed out separately and placed into individualclear receptacles. About 300 ml sterile water was added with stirring.Both active ingredients dissolved well to form transparent solutions.The pH of each of the solutions was then adjusted to pH 7.7-8.5 withhydrochloric acid or sodium hydroxide dropwise. Next, edetate disodiumdehydrate was added to the dexamethasone solution with stirring,followed by the addition of glycerin with stirring, followed by theaddition of hydroxyethyl cellulose (4,800 cps) with stirring. The pH wasadjusted to 8.2 as needed. This dexamethasone solution was then added tothe moxifloxacin solution with stirring to form a moxifloxacin anddexamethasone solution. Last, the benzalkonium chloride solution wasadded to the moxifloxacin and dexamethasone solution with stirring. ThepH was adjusted to 8.2-8.25 as needed. The volume was then brought up to1000 ml with sterile water. The solution was clear and transparent. Thesolution was aseptically filtered and placed into 5 ml steriledroptainers. Testing such as rapid scan for sterility, pyrogenicity, andpotency were carried out.

Example 3

The following procedure was followed to make a homogeneous, aqueoussolution of sodium bromfenac sesquihydrate and dexamethasone sodiumphosphate.

Ingredients Amount Polysorbate 80 liquid 0.5 ml Bromfenac sodiumsesquihydrate powder 0.4025 g Dexamethasone sodium phosphate powder 1.1g Edetate disodium dihydrate powder 0.1 g Hydroxyethyl cellulose powder(4,800 cps) 1 g Benzalkonium chloride solution (0.5%/ml) 5 ml Glycerin18.2 ml Hydrochloric acid (10% solution) for pH varies adjustment Sodiumhydroxide (1% solution) for pH varies adjustment Sterile water up to1000 ml

Preliminary attempts to combine the dry active ingredients sodiumbromfenac sesquihydrate and dexamethasone into one aqueous solutionresulted in significant solubility issues. The resulting mixtureappeared hazy with significant particles visible to the naked eye, whichsettled on the bottom of the receptacle.

Therefore, the active ingredients were weighed out separately and placedinto individual clear receptacles. About 300 ml sterile water was addedwith stirring. Both active ingredients dissolved well to form twotransparent solutions. The pH of each of the solutions was then adjustedto pH 7.7-8.5 with hydrochloric acid or sodium hydroxide dropwise. Next,edetate disodium dehydrate was added to the dexamethasone solution withstirring, followed by the addition of glycerin and hydroxyethylcellulose (4,800 cps), each with stirring afterwards. The pH of each ofthe solutions was then adjusted to pH 7.7-8.5 with hydrochloric acid orsodium hydroxide dropwise. The resulting dexamethasone solution was thenadded to the bromfenac sodium sesquihydrate solution with polysorbate 80and stirring to form a bromfenac and dexamethasone solution. The pH wasadjusted to 8.20-8.25 as needed. Next, the benzalkonium chloridesolution was added to the bromfenac-dexamethasone solution. The pH wasagain adjusted to 8.20-8.25 as needed. The volume was brought up to 1000ml with sterile water. The solution was clear and transparent. Thesolution was aseptically filtered and placed into 5 ml steriledroptainers. Testing such as rapid scan for sterility, pyrogenicity, andpotency were carried out.

Example 4

The solutions were analyzed by LCMS and standard curve analysis toconfirm the identity and quantity of each active ingredient and aresummarized below. Separate stock solutions of moxifloxacin HCI,dexamethasone, and sodium bromfenac were used as standards. Threedifferent samples of solutions containing the three active ingredients,i.e., moxifloxacin HCI, dexamethasone, and sodium bromfenac wereanalyzed for the concentration of moxifloxacin in solution, theconcentration of dexamethasone in solution, and the concentration ofsodium bromfenac in solution.

Concentration in Solution moxifloxacin HCI 5.458 ± 0.211 mg/mldexamethasone sodium phosphate 1.102 + 0.011 mg/ml bromfenac sodium0.0405 + 0.047 mg/ml

Example 5

The pre-treatment regimen for patients who will undergo cataract surgeryis one drop applied to the eye per day for each of three daysimmediately prior to surgery. The post-treatment regimen is one dropapplied to the eye four times a day for twenty days, including the dayof surgery. In some cases, patients have continued the post-treatmentregimen for an additional seven days. In one clinical trial, the use ofthe composition of the present application appears to have eliminatedthe incidence of CME, which is one of the most severe complicationsfollowing cataract surgery.

Although embodiments of the present invention have been described indetail, it will be understood by those skilled in the art that variousmodifications can be made therein without departing from the spirit andscope of the invention as set forth in the appended claims.

This written description uses examples to disclose the invention andalso to enable any person skilled in the art to practice the invention,including making and using any compositions and performing anyincorporated methods. The patentable scope of the invention is definedby the claims, and may include other examples that occur to thoseskilled in the art. Such other examples are intended to be within thescope of the claims if they have elements that do not differ from theliteral language of the claims, or if they include equivalent elementswith insubstantial differences from the literal languages of the claims.

It will be understood that the particular embodiments described hereinare shown by way of illustration and not as limitations of theinvention. The principal features of this invention may be employed invarious embodiments without departing from the scope of the invention.Those of ordinary skill in the art will recognize numerous equivalentsto the specific procedures described herein. Such equivalents areconsidered to be within the scope of this invention and are covered bythe claims.

All of the compositions and/or methods disclosed and claimed herein maybe made and/or executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of the embodiments included herein, it willbe apparent to those of ordinary skill in the art that variations may beapplied to the compositions and/or methods and in the steps or in thesequence of steps of the method described herein without departing fromthe concept, spirit, and scope of the invention. All such similarsubstitutes and modifications apparent to those skilled in the art aredeemed to be within the spirit, scope, and concept of the invention asdefined by the appended claims.

Thus, although there have been described particular embodiments of thepresent invention, it is not intended that such references be construedas limitations upon the scope of this invention except as set forth inthe following claims.

1-20. (canceled)
 21. A composition comprising an aqueous, homogeneoussolution of a quinolone antibiotic and an anti-inflammatory agent,wherein the solution has a pH in the range of about 4.5 to about 8.5 andremains a solution during topical application to an eye of a patient.22. The composition of claim 21, wherein: the quinolone antibiotic ispresent in an amount of about 0.1 to about 1% by weight; and theanti-inflammatory agent is present in an amount of about 0.01 to about1% by weight.
 23. The composition of claim 21, wherein the quinoloneantibiotic comprises moxifloxacin, ciprofloxacin, oflaxacin,norfloxacin, lomefloxecin, derivatives thereof, salts thereof, ormixtures thereof.
 24. The composition of claim 21, wherein the quinoloneantibiotic is moxifloxacin, a salt thereof, a derivative thereof, or amixture thereof.
 25. The composition of claim 24, wherein theanti-inflammatory agent comprises a steroidal agent selected from thegroup consisting of dexamethasone, budensonide, triamcinolone,hydrocortisone, loteprednol, prednisolone, mometasone, fluticasone,rimexolone, fluorometholone, beclomethasone, flunisolide, salts thereof,derivatives thereof, and mixtures thereof.
 26. The composition of claim25, wherein the steroidal agent is dexamethasone, a salt thereof, aderivative thereof, or a mixture thereof.
 27. The composition of claim26, wherein: the quinolone antibiotic is moxifloxacin hydrochloride; andthe steroidal agent is dexamethasone sodium phosphate.
 28. Thecomposition of claim 25, wherein the anti-inflammatory agent furthercomprises a non-steroidal agent selected from the group consisting ofbromfenac, aspirin, nabumetome, etodolac, meclofenamate, ibuprofen,flurbiprofen, diffusional, piroxicam, suproprofen, diclofenac, sulindac,oxyphenbutazone, oxaproazin, ketorolac, naproxen, nepafenac, mefamicacid, ketoprofen, amfenac, fenoprofen, phenylbutazone, indomethacin,cececoxib, nupafant, filaminast, salts thereof, derivatives thereof,hydrates thereof, and mixtures thereof.
 29. The composition of claim 25,wherein the anti-inflammatory agent further comprises a non-steroidalagent selected from the group consisting of bromfenac, bromfenac sodium,bromfenac sodium sesquihydrate, and mixtures thereof.
 30. Thecomposition of claim 28, wherein: the quinolone antibiotic is present inan amount of about 0.1 to about 1% by weight; the steroidal agent ispresent in an amount of about 0.01 to about 1% by weight; and thenon-steroidal agent is present in an amount of about 0.01 to about 1% byweight.
 31. The composition of claim 29, wherein: the quinoloneantibiotic is present in an amount of about 0.5% by weight; thesteroidal agent is present in an amount of about 0.1 to about 1% byweight; and the non-steroidal agent is present in an amount of about0.07 to about 0.08% by weight.
 32. The composition of claim 28, wherein:the steroidal agent is dexamethasone, a salt thereof, a derivativethereof, or a mixture thereof; and the non-steroidal agent is bromfenac,a salt thereof, a derivative thereof, a hydrate thereof, or a mixturethereof.
 33. The composition of claim 32, wherein: the quinoloneantibiotic is moxifloxacin hydrochloride; the steroidal agent is adexamethasone sodium phosphate; and the non-steroidal agent is bromfenacsodium or bromfenac sodium sesquihydrate.
 34. The composition of claim32, wherein: the quinolone antibiotic is present in an amount of about0.5% by weight; the steroidal agent is present in an amount of about0.1% by weight; and the non-steroidal agent is present in an amount ofabout 0.035% by weight.
 35. The composition of claim 28, furthercomprising a compound selected from the group consisting of apreservative, a solubility enhancer, a thickener, a pH moderating agent,a buffer, a humectant, and mixtures thereof.
 36. The composition ofclaim 29, further comprising edetate disodium dihydrate, hydroxyethylcellulose, benzalkonium chloride, a pH moderating agent, and ahumectant.
 37. A method of treating or preventing ophthalmic infectionor inflammation comprising topically applying the composition of claim 1to the eye.
 38. A composition comprising an aqueous, homogeneoussolution of: about 0.5% by weight moxifloxacin, a salt thereof, aderivative thereof, or a mixture thereof; about 1% by weight of asteroidal anti-inflammatory agent; and about 0.07 to about 0.08% byweight of a non-steroidal anti-inflammatory agent selected from thegroup consisting of bromfenac, bromfenac sodium, bromfenac sodiumsesquihydrate, and mixtures thereof; wherein the solution has a pH inthe range of about 4.5 to about 8.5 and remains a solution duringtopical application to an eye of a patient.
 39. A composition comprisingan aqueous, homogeneous solution of: moxifloxacin hydrochloride;dexamethasone sodium phosphate; bromfenac sodium or bromfenac sodiumsesquihydrate; and at least one compound selected from the groupconsisting of a preservative, a solubility enhancer, a thickener, a pHmoderating agent, a buffer, a humectant, and mixtures thereof; whereinthe solution has a pH in the range of about 7.5 to about 8.5 and remainsa solution during topical application to an eye of a patient.
 40. Thecomposition of claim 39, wherein the at least one compound is a mixtureof edetate disodium dihydrate, hydroxyethyl cellulose, benzalkoniumchloride, a pH moderating agent, and a humectant.